Background <p>Growth factor-independent-1 transcription repressor (GFI1) is crucial for determining the differentiation and fate of exhausted CD8⁺ T cells and affects immunotherapy outcomes. However, the effects of tumor cell–intrinsic GFI1 on antitumor immunity and the response to immunotherapy remain unknown.</p> Methods <p>The tumor cell-intrinsic expression of GFI1 was examined via RT‒qPCR and Western blotting. Immunohistochemical staining of tumor tissues was performed to assess the relationships among GFI1, CD8, and MHC I expression. A syngeneic mouse model and clinical tumor samples from NSCLC patients undergoing immunochemotherapy were used to evaluate how tumor cell-intrinsic GFI1 affects the response to immunotherapy. Additionally, techniques such as flow cytometry, immunoprecipitation, ChIP-qPCR, immunofluorescence, and both loss- and gain-of-function approaches were employed to investigate the underlying mechanisms involved.</p> Results <p>Tumor-intrinsic GFI1 expression was positively associated with MHC I expression and the infiltration of CD8⁺ T cells. Tumors with higher GFI1 levels showed a significantly better response to immunotherapy. The overexpression of GFI1 in tumor cells increases MHC-I expression in a STAT1-dependent manner. Mechanistic analysis revealed that GFI1 inhibits HDAC1 activity in tumor cells by promoting its export to the cytoplasm, thereby increasing H3K9 acetylation and the transcription of STAT1 and MHC-I. Additionally, phenformin, an AMPK activator, increases GFI1 levels by downregulating EZH2 expression. Compared with anti-PD-L1 therapy alone, combining phenformin with anti-PD-L1 therapy enhances antitumor effects.</p> Conclusions <p>This study demonstrated the crucial role of tumor-intrinsic GFI1 in enhancing antitumor immune responses, suggesting a new target for increasing the effectiveness of PD-1/PD-L1 blockade.</p>